Dopamine analog amide

ABSTRACT

The invention involves the formation of a prodrug from a fatty acid carrier and a neuroactive drug. The prodrug is stable in the environment of both the stomach and the bloodstream and may be delivered by ingestion. The prodrug passes readily through the blood brain barrier. Once in the central nervous system, the prodrug is hydrolyzed into the fatty acid carrier and the drug to release the drug. 
     In a preferred embodiment, the carrier is 4, 7, 10, 13, 16, 19 docosahexa-enoic acid and the drug is dopamine. Both are normal components of the central nervous system. The covalent bond between the drug and the carrier preferably is an amide bond, which bond may survive the conditions in the stomach. Thus, the prodrug may be ingested and will not be hydrolyzed completely into the carrier molecule and drug molecule in the stomach.

RELATED APPLICATIONS

This application is a continuation (CIP) of prior application Ser. No.:08/462,820, filed Jun. 5, 1995 and which will issue on Nov. 30, 1999under U.S. Pat. No. 5,994,392, which is a continuation of U.S. Ser. No.08/080,675, filed Jun. 21, 1993 now abandoned which is a continuation ofU.S. Ser. No. 07/952,191, filed Sep. 28, 1992 now abandoned which is acontinuation of U.S. Ser. No. 07/557,329, filed Sep. 4, 1990 nowabandoned which is a continuation-in-part of 07/535,812, filed Jun. 11,1990, and now abandoned, which is a continuation of U.S. Ser. No.07/315,134, filed Feb. 24, 1989, and now U.S. Pat. No. 4,933,324, whichis a continuation-in-part of U.S. Ser. No. 07/160,667, filed Feb. 26,1988, now U.S. Pat. No. 4,939,174, Ser. No. 08/080,675, filed on Jun.21, 1993. The contents of all of the above-identified applications arehereby incorporated by reference.

The contents of co-pending applications Ser. Nos. 07/517,158 and07/517,159 both filed on May 1, 1990, now pending, are also expresslyincorporated by reference.

BACKGROUND OF THE INVENTION

This invention relates in general to the fields of medicine,pharmacology and biochemistry, and more particularly to prodrugs capableof delivering a drug across the blood brain barrier including a prodrugmade of a fatty acid-dopamine conjugate that is effective as anappetite-suppressant.

There are many obstacles to developing treatments which allow thedelivery of a drug to an active site in the body. Ingestion of a drugoften is not possible because many drugs will not survive theenvironment of the stomach. Thus, easy and safe self-administration ofmany drugs is not available. A drug, of course, may be injected directlyinto the blood stream of a patient. However, because some drugs do notsurvive for very long in the bloodstream, frequent injections at greatinconvenience to a patient may be necessary. The inability of a drug tosurvive in the bloodstream may be overcome in certain instances byincreasing the dosage or by increasing the frequency of administration.However, increasing the dosage can result in undesirable side effectsand increasing the frequency of administration only adds inconvenience.

The delivery of a neuroactive drug to the central nervous system (CNS)via the bloodstream involves an extraordinary obstacle; the drug must becapable of crossing the blood brain barrier. The blood brain barrier mayloosely be regarded as a biological exclusion barrier involving bothpassive and active transport, which barrier controls the exchange ofmaterials between the plasma and the central nervous system. Many drugsubstances are unable to pass through this barrier in efficaciousamounts or at all. Thus, there is a serious need for a mechanism forintroducing a drug across the blood brain barrier and into the CNS.

Efforts have been taken to enhance the ability of certain drugs to passthrough the blood brain barrier. Investigators have attempted to maskthe polar groups of a drug to produce more lipophilic derivatives, aslipophilic compounds are believed to cross the blood brain barrier morereadily than hydrophilic compounds. For example, diacetyl and triacetylesters of dopamine and norepinephrine have been made to mask thehydroxyl groups of these compounds and produce more lipophilicderivatives. This investigator has formed an ester bond betweenγ-aminobutyric acid, a drug which is unable to cross the blood brainbarrier, and a “carrier” molecule having an enhanced ability to crossthe blood brain barrier. The carrier-drug conjugate shares with thecarrier the ability to cross the blood brain barrier. Once in the CNS,the conjugate itself may be active. However, it is believed that theester bond between the carrier and drug is broken in the CNS to releasethe drug in its native form. This may occur due to the general presenceof active, non-specific esterases throughout the CNS.

Appetite-suppressant drugs have been sought for many years. Dopamine isbelieved to be involved in the neuropathways responsible forappetite-suppression. Dopamine itself is not used as anappetite-suppressant because it does not readily cross the blood brainbarrier. Drugs which closely resemble the structure of dopamine andwhich will cross the blood brain barrier have been used with somesuccess as alternatives to dopamine.

The most widely used appetite-suppressant drugs are generally based onderivatives of amphetamine, which structurally resembles dopamine and assome properties which correspond to a dopamine agonist. Unlike dopamine,sufficient uptake of amphetamines across the blood brain barrier doesoccur to produce a biological effect. However, amphetamines have manyserious cardiovascular and neuropsychiatric side effects, as well as atendency to develop tolerance, the increasing resistance to the usualeffect of the drug over time. At worst, tolerance to a drug renders thedrug useless. At best, tolerance generally encourages the use of higherdrug doses, increasing the possibility of undesirable side effects. Inanimal tests, tolerance to certain of these amphetamine derivatives hasbeen shown to develop within one day after one dose. Using amphetamineitself, tolerance has been shown to develop within 3-15 days.

Dopamine is also known to play a crucial role in several neurologicallyrelated disorders. For example, Parkinsonism is a striatal dopaminedeficiency. Because dopamine (and related catacholamines) essentiallydoes not cross the blood brain barrier Parkinsonism is treated withL-Dopa, a precursor to Dopamine. This treatment, however, is at theexpense of a wide variety of undesireable side effects, includinghallucination. Dopamine agonists which are used in the treatment ofhyperprolactinemia associated with pituitary adenomas or amenorrhea alsoinduce undesireable side effects. Thus, there is a serious need fordelivering dopamine itself or dopaminergic agents directly to the brain.

SUMMARY OF THE INVENTION

The invention involves the formation of a prodrug from a fatty acidcarrier and a drug. The prodrug is believed to be stable in theenvironment of both the stomach and the bloodstream and may be deliveredby ingestion. The prodrug passes readily through the blood brainbarrier. The prodrug has a brain penetration index of at least two timesthe brain penetration index of the drug alone. Once in the centralnervous system, the prodrug, which preferably is inactive, is hydrolyzedinto the fatty acid carrier and the drug. The carrier preferably is anormal component of the central nervous system and is inactive andharmless. The drug, once released from the fatty acid carrier, isactive.

Preferably, the fatty acid carrier is a partially-saturated straightchain molecule having between about 16 and 26 carbon atoms, and morepreferably 20 and 24 carbon atoms. Most preferably, the carrier is 4, 7,10, 13, 16, 19 docosahexa-enoic acid.

The covalent bond between the drug and the carrier preferably is anamide bond, which bond may survive the conditions in the stomach. Thus,the prodrug may be ingested and will not be hydrolyzed completely intothe carrier molecule and drug molecule in the stomach.

The prodrugs of the invention preferably are formed of fatty acidsconjugated to neurotransmitters, anti-aids substances, anti-cancersubstances, antibiotics, peptides, anti-viral substances, anti-addictionsubstances, anti-psychotic substances and anti-inflammatory substances.The prodrugs of the invention further may be provided in combinationwith pharmaceutically-acceptable carriers to form pharmaceuticalpreparations. Tablets and capsules are particularly preferredpreparations.

In one preferred embodiment, the drug is dopamine, also a normalcomponent of the central nervous system and the prodrug is

Compound 8739 may be expressed alternatively as

This compound has been found to be useful as an appetite-suppressant. Italso is believed to have anti-psychotic properties. It has a brainpenetration index of 33, a value eight times that of dopamine. It isinactive until it crosses the blood brain barrier and hydrolyzes torelease dopamine into the central nervous system. The drug suppressesappetite without harmful side effects and without inducing tolerance.The prodrug also appears to be capable of delivering the dopaminepreferentially into the synaptosomal membranes, the location of the drugaction.

An object of the invention is to provide a carrier molecule capable ofbeing combined with a drug to form a prodrug that will readily cross theblood brain barrier and allow release of the drug into the centralnervous system.

Another object of the invention is to provide a prodrug that is stablein the environment of the stomach and in the bloodstream.

Another object of the invention is to provide pharmalogical compositionscomprising amides of the carriers of the invention combined with drugs,including dopamine.

Another object of the invention is to provide a method for delivering aneuroactive drug, including dopamine, to the central nervous system.

Another object of the invention is to provide pharmaceuticalpreparations containing preselected doses of the prodrugs of theinvention.

An object of the invention to provide an appetite-suppressant drug thatwill not induce tolerance and will not cause harmful side effects.

Another object of the invention is to provide an amide derivative ofdopamine with biological activity useful in the regulation of appetite.

Yet a further object of the invention is to provide a method fortreating neurological disorders in general, and specifically forintroducing dopamine and dopaminergic agents into the brain to treatdopamine related disorders.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of the produrg of the preferredembodiment on motor activity and food intake of mice;

FIG. 2 is a graph comparing the effect on motor activity in mice ofvarying the mode of delivery of the prodrug of the preferred embodiment;

FIG. 3 is a graph showing the effect on motor activity in mice of longterm administration of the prodrug of the preferred embodiment; and

FIG. 4 is a graph comparing the effect on food intake in mice of longterm administration of the prodrug of the perferred embodiment withamphetamine.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS AND OF THE DRAWINGS

The most preferred embodiment of the invention is

This compound has extraordinary and unexpected properties. Thiscompound, hereinafter called compound 8739, is inactive until it crossesthe blood brain barrier to release dopamine into the central nervoussystem (CNS). Unlike dopamine, compound 8739 survives sufficiently inthe environment of the stomach and the bloodstream and therefore can beadministered orally.

Compound 8739 has an enhanced ability to cross the blood brain barrier,with a brain penetration index (BPI) of about 33, as compared to about 4for dopamine. It is inactive as a prodrug in that it does not bind toeither D-1 or D-2 dopamine receptors. Rather, once in the centralnervous system, dopamine is released as an active fragment of compound8739. In addition, compound 8739 is taken up into the synaptosomalmembranes preferentially, the synaptosomal membranes being the site ofactivity for the dopamine. This property may contribute to thecompound's desirable properties.

Once dopamine is released as an active fragment, it produces effects onfood intake and on general locomotor activity in mice in adose-dependent manner. Food intake decreased by as much as 50% at thehigher doses. Open field activity also decreased by about 50%,indicating that, unlike amphetimine, compound 8739 has a tranquilizingeffect rather than an activity-enhancing effect.

Many of the undesirable side effects of amphetamines were absent.Compound 8739 failed to induce “stereotypy”, failed to produce an effecton “circling behavior” of striatal lesioned rats, and failed todemonstrate any diverse effects on motor function or motivation in testanimals. Remarkably, there was no indication of tolerance. Failure toinduce tolerance was unexpected.

Another favorable property of compound 8739 was unexpected. Previousreports have demonstrated that fatty acids, including the fatty acid ofcompound 8739, induce swelling of the brain. Chan, P. H., Fishman, R.A., SCIENCE, Vol. 20, 358-360 (1978). Compound 8739 (and another prodrugcompound made from a straight chain fatty acid having 20 carbon atomsand 4 double bonds), however, did not induce any swelling.

EXPERIMENTAL DATA

Synthesis of the Compound 8739

Compound 8730 is synthesized as follows:

DHA is first converted to DHA anhydride in the presence of dicyclohexylcarbodiimide. This is then reacted with dopamine in the presence of4-dimethylaminopyridine as the acid acceptor in tetrahydrofuran. In atypical experiment 300 mg of DHA (0.009 M) was dissolved in a mixture of3 ml hexane and 4 ml benzene and stirred under nitrogen. Next, asolution of 0.00615 M of dicyclohexyl carbodiimide in 4 ml benzene(0.1267 g) was stirred together with the DHA for 3 hr at roomtemperature. A white precipitate of dicyclohexyl urea formed as thereaction proceeded. The dicyclohexyl urea was filtered off to give aclear solution of the anhydride in benzene. This was concentrated downto 2 ml in a rotary evaporator and diluted with 10 ml of tetrahydrofuran(dry). The freshly prepared anhydride was then added to a solution ofdopamine hydrobromide (0.1053 g) (or 0.005 M) in the presence of 0.009 Mof 4-diethylaminopyridine (0.098 g). The initially cloudy mixture afterstirring for 30 min at room temperature gave a mixture of a clear liquidand a brown precipitate. At the end of the reaction, 0.2 ml of water wasadded to the mixture, and stirring was continued for an additional 30min to completely hydrolyze any remaining unreacted anhydride. Theliquid phase was isolated and evaporated to dryness to yield a brownviscous solid. This was then dissolved in 70% ethanol in water (25 ml),and the solution was then passed through a mixed-bed ion exchange resincontaining a strong acidic resin based on polystyrene sulfonic acid anda strong basic resin based on quanternary amonium substituents such astetramethyl amonimum hydroxide (RG501, Fisher Scientific, Cambridge,Mass.) using 90% ethanol in water as the eluent. This resin removes fromthe mixture unreacted dopamine, dimethylaminopyridine, as well as theliberated DHA molecule. The effluent from the column (a pale yellowsolution) was then evaporated in a rotary evaporator to give a solid.The product was recrystallized from aqueous ethanol (yield=75%).

The structure of compound 8739 (III) was established by massspectrometry. The major peak (95% of the compound) consisted of aproduct with a mass of 550. Fragment analysis by mass spectrometry andcarbon, hydrogen, infrared, and NMR spectra confirmed the structure ofcompound 8739.

A trimethyl silyl derivative (compound IV) of the two hydroxyl groups ofdopamine was also synthesized to further confirm the structure ofcompound 8739. This derivative was shown to have the correct mass of608.

Compound 8739 was stored as a solution in ethanol (12 mg/ml) in thecold. Aliquots of this were evaported to dryness and dissolved in 15%propylene glycol in 0.1 M NaHCO₃ for use in biological activity tests.

Brain Uptake Studies

A brain penetration index (BPI) determination was used as a criterionfor measuring the capacity of a compound to cross the blood brainbarrier. Shashoua, V. E., Jacob, J. N., Ridge, R., Campbell, A. andBaldessarini, R. J., J. Med. Chem. 27, 659 (1984). The BPI is a measureof the uptake of a compound by the brain relative to its uptake by theliver. The liver is chosen as a reference since it is an organ which hasno barrier to diffusable molecules present in the blood. Moreover, evenif subcutaneous injections are used, the injected material tends toremain largely at the site of the injection and slowly diffuse into thecirculation. Therefore, the amount of material in the liver will reflectthe amount available rather than the initial dose injected.

Measurements of the quantity of the drug present in the brain and liverwere measured at five minutes after a subcutaneous injection and wereused to calculate the BPI, the equation being:

BPI=[brain]/[liver]×100

For these measurements, compound 8739 was synthesized from ¹⁴C-labeleddopamine. Thirty pCi of dopamine labeled hydrochloride was mixed with0.1 mg of unlabeled dopamine hydrobromide and reacted with a two-foldexcess of DHA anhydride. The reaction was run overnight; the product wasthen evaporated to dryness and dissolved in ethanol. The compound wasidentified as 8739 by its migration properties on thin-layerchromatography using chloroform:methanol as one solvent anddimethylformamide (DMF) as the other. The migration properties wereequivalent to those of the unlabeled product.

¹⁴C-labeled 8739 was dissolved in 15% propylene glycol in 0.1 M NaHCO₃and then injected subcutaneously (s.c.) into male balb C mice (20±2 g).After 5 minutes the animals were sacrificed by cervical fracture and thebrain and liver were dissected out, weighed and homogenized in 8 and 10ml of Brain Protein Solvent (BPS) buffer, respectively [BPS=2% sodiumdodecyl sulfate in 0.03 M Tris, 6 M urea, pH 7.6, 0.01 M EDTA and 0.14 NNaCl]. Aliquots were then counted for ¹⁴C content in 10 ml of a liquidscintillation fluid, Liquiscent (National Diagnostic Company,Somerville, N.J.) using a Beckman liquid scintillation counter. The ¹⁴Ccounts were then used to calculate the total quantity of compound 8739present in the brain per gram of tissue as compared to that in theliver. The ratio of the amount in the brain as a percent of that presentin liver was determined.

Results

TABLE I Compound Brain (cpm/g) Liver (cpm/g) BPI Value (%) 8739 13054300 30 8739 1297 3931 33 Dopamine 4 D-glucose 33

The results indicate that the brain uptake of compound 8739 is overeight-fold higher than the brain uptake for dopamine. Compound 8739 alsocompares favorably with glucose whch is reported in the literature tohave a BPI index of 33.

Studies of the Pattern of Distribution of 8739 in Membranes of theCentral Nervous System

The utility of a drug may be determined by its ability to be taken upselectively by the particular regions of the brain upon which the drugacts. A study was made to determine the pattern of distribution ofcompound 8739 in the various membranes in the central nervous system.Approximately 2×10⁶ counts of ¹⁴C-labeled 8739 in 0.3 ml of 15%propylene glycol in 0.1 M NaHCO₃ was injected subcutaneously into testmice (20±2 g). After 30 minutes the animals were sacrificed by cervicalfracture; the brain was then removed and homogenized in 4 ml of isotonicmedium (0.14 N NaCl, 0.03 M Tris pH 7.4 containing 1.5 mM calciumacetate) according to the method of Whittaker (Whitaker V. P. BiochemJ., 72 694-706 [1959]). The fraction P1 containing nuclear and cellmembrane components was sedimented for 5 min at 2,500 rpm at 0° C. Thesupernatant containing the crude synaptosomal fraction was nextcentrifuged at 13,000 rpm for 30 min to yield a pellet containing thecrude synaptosomal fraction (P2). P1 and P2 were then dissolved in BPS,and the amount of label and protein in each fraction was determined.

Results

TABLE II CPM/mg Protein after 30 min of Uptake P₁ (Nuclear and P₂ CellMembrane (Crude Synapto- Expt. No. Fraction) somal Fraction) P₂/P₁ 1 2.75.2 1.9 2 2.7 5.6 2.1 3 4.19 12.5 2.9

As shown in Table II, the uptake of compound 8739 into the crudesynaptosomal fraction (P2) was greater by a factor of an average of 2.3than in the P1 fraction (nuclear and cell membrane fraction). Thissuggests that there is a preferential concentration of the compound intothe synaptic fraction P2, indicating that 8739 is more highly associatedwith nerve endings, as would be expected from the natural distributionof DHA in lipid glycerides in such membranes.

Pharmacological Properties

Open-field motor activity measurement

The effect of compound 8739 on general motor activity was determined.The general motor activity of balb-c mice was measured in a Stoeltingelectronic activity monitor apparatus during a 90-min period followingan intraperitoneal injection of the compound as a solution in 15%propylene glycol in 0.1 M NaHCO₃. A detailed description of theapparatus is reported in Stewart R. J., Campbell A., Spark G. andBalessarini R. J. Psychopharmacol. 60, 281 (1979).

The test group (six mice) received an i.p. injection of the drug in avehicle (15% propylene glycol in 0.1 M NaHCO₃, a total volume of betweenabout 1-0.3 ml.). The six control mice received the same volume ofvehicle, but no drug. The results (Shown in FIG. 1,) are expressed asthe percent decrease in open-field activity-for the test group versusthe control group. The results indicate that compound 8739 depresses theactivity of the mice by as much as 50%, demonstrating that compound 8739is biologically active following its uptake into the brain. The responsewas dose dependant with higher doses of compound 8739 resulting in agreater decrease in general motor activity.

Food Consumption Measurements

The effect of compound 8739 on food consumption was determined forbalb-c mice that were food deprived for 24 hr, with water freelyavailable. The six test mice were given an i.p. injection of compound8739 as a solution in 15% propylene glycol in 0.1 M NaHCO₃, a totalvolume of between about 0.1-0.3 ml. The six control mice received thesame volume of vehicle, but no drug. The quantity of “mouse chow” eatenduring the 60-min period following the injections was determined. Theresults, also shown in FIG. 1, are expressed as the percent decrease infood consumption for the test group versus the control group. Theresults indicate that compound 8739 is an appetite suppressant (40-50%decrease in food intake). The decrease was dose dependent, with higherdoses of compound 8739 causing greater decrease in food intake. The sameexperiment was conducted using oral administration of compound 8739. Theresults were the same.

Determination of the Effect of Mode of Delivery of Compound 8739 on OpenField Activity

The effects of the mode of delivery of Compound 8739 (oral vs. i.p.) onthe general open-field activity of mice (n=6) was assessed. As shown inFIG. 2, the drug was as active when ingested as when injected. A 40-50%decrease in activity occurred when either delivery method was employed.No significant changes in open-field activity occurred when either thecarrier molecule (T) or dopamine (DA) is administered at the same dose.

Evaluation of Circling Behavior

Dopamine agonists such as apomorphine and amphetamine cause circlingbehavior in animals with nigrostriatal lesions. Compound 8739 releasesdopamine following proteolysis by central nervous system enzymes. It wasexpected that compound 8739 would cause circling behavior in animalswith nigrostriatal lesions in a manner similar to that of dopamineagonists.

Unilateral nigrostriatal lesions in rats were produced by administeringunilateral injections of 6-OH dopamine into the nigrostriatum pathway.Seven days later, these animals were i.p. injected with the test drugsand circling behavior was recorded as rotations per minute during a30-min period in the test apparatus, Ungerstedt U. and Arbathnott G. W.,Brain Res. 24, 485-493 (1970).

TABLE III AVERAGE ROTATION SCORES DOSE (Rotations/minutes) COMPOUND(mg/kg) Ipsilateral Contralateral Apomorphine 0.1 0.1 4.8 ″ 0.5 0 13.7Amphetamine 3.0 2.5 0.4 ″ 5.0 3.32 0.32 8739 34 0.08 0.05 ″ 51 0.08 0.12Controls (uninjected) 0.10 0.12

Apomorphine produced a rapid circling behavior to the contralateral sideof the lesion, whereas amphetamine caused circling rapidly to theipsilateral lesion side. The enhanced contralateral rotations forapomorphine and ipsilateral rotations for amphetamine are consistentwith the reported results for these dopaminme agonists. Compound 8739did not evoke this behavior. Rather, the rate of circling was very low,approximately the same as that observed for uninjected controls. Thus itappears that compound 8739 does not evoke all of the effects (sideeffects) of dopamine agonists.

Self-stimulation Data

A self-stimulation test has been used to measure the capacity of a givenpharmacological agent to inhibit rats from receiving self-inducedelectrical stimuli via electrodes implanted in their brains (lateralhypothalamus). Stellar J. R. and Stellar E., The Neurobiology ofMotivation and Reward, Springer-Verlag, New York, 1985. Animals willpress levers to receive a pulse of current from the implanted electrodeat a rate dependent upon the quantity of current that is being deliveredas a reward. It is believed that the reward obtained results from therelease of dopamine caused by the electrical stimulation (Stellar J.R.). The intensity of the current is varied by raising the frequency atwhich 250 mV pulses (0.1 msec duration) are delivered during a 0.5-sectime span. A plot of the log of the frequency of the delivered pulsesvs. the rate of level press for an animal gives the self-stimulationreward curve. Injections of drugs which have a neuroleptic-type ortranquilizing effect can depress the rate of self-stimulation, shiftingthe response to higher current deliveries. Pemozide can give a depressedrate by about 90%. Investigations of the efficacy of compound 8739 bythis test showed that the compound had no effect on either the reward orthe motor aspect of the self-stimulation parameters. This indicates thatcompound 8739, even though it is able to cause a decrease in the generalmotor activity of an animal, has no effect on the motivation or thecapacity to press for the “current reward”. The animal continues topress the lever at the rate equivalent to a non-injected control or onereceiving the vehicle alone. Thus, compound 8739 does not produce yetanother effect (side effect) characteristic of dopamine agonists.

Tests for Tolerance

The effects of daily i.p. injections of compound 8739 at a dose of 20mg/kg on open field activity and food consumption was tested todetermine whether tolerance to the drug was induced over time. The openfield activity of six test mice and six control mice was monitored forfive days. Then, the test mice were given i.p. injections of the drug ina vehicle and the control mice were given i.p. injections of the vehicleonly. This regimen was carried out for a 21 day test period. At the endof the 21 days, the vehicle alone was given daily to both test andcontrol mice and open field activity and food consumption was monitoredfor an additional six days.

FIG. 3 plots the percent decrease in open field activity of the testmice (n=6) as compared to the controls (n=6). As shown in FIG. 3, thelevel of activity prior to injections was the same for both groups. Uponinitation of injections, there was a 30% to 60% decrease in open fieldactivity. This decrease remained fairly constant for the entire 21 daysof injections indicating that no tolerance was induced by repeatedinjections during the test period. Beginning at day 22 and daily untilday 27, vehicle alone was given to both groups. As shown in FIG. 3,activity returned to its predrug level when the drug administration wasdiscontinued.

The effect of long-term administration of compound 8739 on the patternof food consumption of mice was compared to the long-term effects of theadministration of amphetamine. Daily i.p. injections of compound 8739(20 mg/kg) were given to test animals and daily i.p. injections ofamphetamine (2 mg/kg) were given to control animals for 21 days. 24hours after the first injection and about every five days after that,the animals were food-deprived for 24 hours with water freely available,and then were tested for food consumption for one-hour beginning at fiveminutes after receiving their daily injection.

FIG. 4 plots the percent decrease in food consumption versus time. Foramphetamine injected mice, the decrease in food intake due to theamphetamine virtually disappeared after 15 days indicating completetolerance to the dosage employed. With compound 8739 injected mice, theapproximately 40%-50% decrease in food intake persisted for the entire21 day period indicating no tolerance had developed.

The pharmacological properties of compound 8739 appear to becharacteristic of a partial dopamine agonist. Compound 8739 depressesthe general motor activity and food intake behavior in mice. However,many of the properties which might be considered as “side effects” ofdopamine agonists such as amphetamine and apomorphine are not obtained.Thus, circling behavior in nigrostriatal lesion to animals andmotivational effects in self-stimulation experiments do not resultfollowing the administration of compound 8739.

Compound 8739 has been administered orally without any apparent loss inefficacy, and, therefore, is stable. Moreover, the compound does notbind to the dopamine receptors in receptor binding assays. Thus, thedrug appears to be inactive until proteolysis releases the activedopamine. While the mechanism of action of the drug is not fullyunderstood, and the inventor does not intend to be bound by any theory,it is believed that the localization of uptake into synaptic endings maycause site-specific release of the active dopamine from the prodrug.Such site-specific release could be responsible for some of thefavorable properties of the drug. Further, that the carrier and drug arenatural constituents of the CNS may contribute to compound 8739'sdesirable properties.

The invention is not limited to the foregoing description of thepreferred embodiment. Thus, it is contemplated that the specific carrierdescribed in the preferred embodiment and other carriers of theinvention described in greater detail below are capable of being linkedby an amide bond or otherwise to other drugs including otherneurotransmitters, analogues of neurotransmitters including analogues ofdopamine and other neuroactive substances to facilitate the delivery ofthe substance across the blood brain barrier and into the CNS. The termdrug thus is intended to include agents that may be used on oradministered to animals as an aid in diagnosis, treatment or preventionof disease or other abnormal conditions, for relief of pain orsuffering, or to control, affect, maintain or improve a physiological orpathological condition. The term animal is intended to include thoseanimals having central nervous system, and particularly those with ablood brain barrier and susceptible to the problems encountered whenattempting to transport drugs across the blood brain barrier. Examplesof amimals includes mammals, e.g. humans, domestic household, sport orfarm animals such as sheep, goats, cattle, horses, mice, rats, guineapigs, fish, aviens, reptiles, and zoo animals.

The preferred carrier has been coupled, for example, to a Met-enkephalinderivative of the following formula YGGFMK, in which the carrier iscoupled via a peptide bond to the gamma amino group of lysine (K). Thiscompound, when injected into mice at a dose of 20 mg/kg body weight, waseffective as an analgesic at a tenfold lower dose as compared to thecarrier free Met-enkephalin (Paw Lift Latency Hotplate Test). Thepreferred carrier has also been coupled via an amide bond to the freeamino group of norepinephrin. This compound had an eightfold higher BPIthan norepinephirn.

Classes of drugs which are intended to be included within this inventioninclude neurotransmitters, anorectic compounds, anti-aids substances,anti-cancer substances, antibiotics, drugs effecting adenosineconcentrations, adrenergics, cholinergics, benzodiazepines, drugseffecting cocaine receptors, drugs effecting cyclic nucleotide pathways,dopaminergics, enzyme inhibitors, excitatory amino acids, GABA-ergics,histaminergics, ion channel modulators, neurotoxins, opioids, drugseffecting PCP/sigma receptors, cyrotonergics, hypnotics, psychicenergizers, tranquilizers, benzodiazepines, anti-convulsants, musclerelaxants, anti-parkinson agents, anti-hypertensives, analgesics,anti-pyretics and anti-inflammatory agents, local anesthetics,anti-spasmodics and muscle contractants, prostaglandins,anti-bacterials, anti-septics, anti-depressants, anti-migrainepreparations, central nervous system stimulants, imaging agents,specific targeting agents, proteins, peptides, anti-viral agents,anti-psychotic agents, anti-addiction agents and anti-emetics.

Neurotransmitters are substances which are released from a neuron onexcitation and travel to either inhibit or excite a target cell.Examples of neurotransmitters include dopamine, serotonin,γ-aminobutyric acid, norepinephrine, histamine, acetylcholine, andepinephrine.

Neuroactive amino acids include amino acids having at least someactivity in the brain. Examples of neuroactive amino acids includeglycine, aspartic acid, glutamic acid and taurine.

Anorectic compounds are substances which reduce or diminsh appetite.Examples of such compounds include amphetamine, phefluoramine, anddiethylpropion. Although the CNS uptake of the anorectic compounds issatisfactory, when these compounds are coupled to the preferred carrierslocalized delivery of these compounds into the synaptosomal membranes ofthe CNS is facilitated.

Anti-AIDS substances are substances used to treat or prevent AutoimmuneDeficiency Syndrome (AIDS). Examples of such substances include CD4,3′-azido-3′-deoxythymidine (AZT), 9-(2-hydroxyethoxymethyl )-guanineacyclovir (acyclovir), phosphonoformic acid, 1-adamantanamine, peptideT, and 2′,3′ dideoxycytidine.

Anti-cancer substances are substances used to treat or prevent cancer.Examples of such substances include methotrexate, cisplatin, prednisone,hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrolacetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosteronepropionate, fluoxymesterone, vinblastine (VLB), vincristine, vindesine,etoposide, teniposide, dactinomycin (actinomycin D), daunorubicin(daunomycin; rubidomycin), doxorubicin, bieomycin, plicamycin(mithramycin), mitomycin (mitomycin C), -asparaginase, hydroxyurea,procarbazine (N-methylhydrazine, MIH), mitotane, aminoglutethimide,mechlorethamine, cyclophosphamide, melphalan ( -sarcolysin), uracilmustard, chlorambucil, busulfan, carmustine (BCNU), lomusline (CCNU),semustine (methyl-CCNU), streptuzocin (steptozotocin), dacarbazine(DTIC: dimethyltriazenomidazolecarboxamide), methotrexate(amethopterin), fluorouracil (5-fluorouracil: 5-FU), cytarabine(cytosine arabinoxide), mercaptopurine (6-mercaptopurine: 6-MP),thioguanine (6-thioguanine: TG).

Antibiotics are art recognized and are substances which inhibit thegrowth of or kill microorganisms. Antibiotics can be producedsynthetically or by microorganisms. Examples of antibiotics includepennicillin, tetracycline, minocycline, doxycycline, vanomycin,bacitracin, kanamycin, neomycin, erythromicin and cephalosporins.Examples of cephalosporins include cephalothin (keflin, seffin),cephapirin (cefadyl), cefazolin (ancef, kefzol), cephalexin (keflex),cephradine (anspor, velosef), cefadroxil (duricef, ultracef),cefamandole (mandol), cefoxitin (mefoxin), cefaclor (ceclor), cefuroxime(zinacef), cefonicid (monocid), ceforanide (precef), cefotaxime(claforan), moxalactam (moxam), ceftizoxime (cefizox), ceftriaxone(rocephin), and cefoperazone (cefobid).

Drugs effecting adenosine concentration include both adenosine agonistsand adenosine antagonists. Examples of adenosine agonists includeadenosine, adenosine amine congener (ADAC), N⁶-benzyladenosine,2-chloroadenosine, 2-phenylamino adenosine (CV-1808),N⁶-cyclohexyladenosine (CHA), N⁶-cyclopentyladenosine (CPA),5′-(N-cyclopropyl)-carboxamidoadenosine,1-deaza-2-chloro-N⁶-cyclopentyladenosine,N⁶-[20(3,5-dimethoxyphenyl)-2-(2-methylphenyl)]adenosine (DPMA),N⁶-(2S)-[2-endo-norbornyl]adenosine (ENBA),5′-N-ethylcarboxamidoadenosine (NECA), N⁶-methyladenosine,5′-N-methylcarboxamidoadenosine, 1-methylisoguanosine, 2-methylthio-ATP,N⁶-phenyladenosine, N⁶-phenylethyladenosine,N⁶-(2-phenylisopropyl)adenosine R(−) isomer, andS(+)-N⁶-(2-phenylisopropyl)adenosine.

Adenosine antagonists include aminophylline,7-(β-chloroethyl)theophylline, 8-cyclopentyl-1,3-dimethylxanthine,8-cyclopentyl-1,3-dipropylxanthine, 1,3-diethyl-8-phenylxanthine,1,3-dimethylxanthine (theophylline), 1,7-dimethylxanthine(paraxanthine), 3,7-dimethylxanthine (theobromine),1,3-dipropyl-7-methylxanthine, 1,3-dipropyl-8-p-sulfophenylxanthine,7-(β-hydroxyethyl)theophylline, 3-isobutyl-1-methylxanthne (IBMX),1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX),8-phenyltheophylline, 3-(n-propyl)-xanthine (enprofylline),8-(p-sulfophenyl)-theophylline, 1,3,7-trimethylxanthine (caffeine),xanthine amine congener (XAC). Other drugs effecting adenosineconcentrations include (R)-2-azido-N⁶-p-hydroxyphenylisopropyl-adenosine(AHPIA), and dipyridamole.

Adrenergics are compounds that are agonists or antagonists of substancescapable of stimulating or activating nerve systems that are responsiveto norephinephrine and ephinephrine. Adrenergics include both adrenergicagonists and antagonists. Examples of adrenergic agonists includealbuterol hemisulfate (salbutamol), p-aminoclonidine HCl,4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride, clonidine HCl, ephedrine HCl, (−)-, epinephrinebitartrate, 6-fluoronorepinephrine HCl, isoproterenol bitartrate,(−)-,isoproterenol bitartrate,(+)-, isoproterenol HCl, (+)-, norepinephrineHCl, octopamine,(±)-, and p-iodoclonidine HCl.

Examples of adrenergic antagonists include alprenolol HCl, bromoacetylalprenolol methane (BAAM), benextramine HCl, benoxathian HCl, efaroxan,idazoxan, phenoxybenzamine HCl, phentolamine mesylate, pindolol,prazosin HCl, propranolol HCl, (−)-, propranolol HCl, (+)-, propranololHCl,(+)-, rauwolscine HCl,2-[2-(2-methoxy-1,4-benzodioxanyl)]imidazoline HCl,2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride,yohimbine HCl. Other adrenergics include amphetamine sulfate,(+)-,amphetamine sulfate,(−)-, p-azidoclonidine oxalate, bretylium tosylate,chloroethylclonidine HCl, diethylpropion HCl,N-(2-chlorethyl)-N-ethyl-2-bromobenzylamine hydrochloride, metanephrineHCl, methamphetamine HCl, (+)-, methamphetamine HCl, (−)-,4-hydroxy-3-methoxyphenylglycol piperazinesalt,3-methoxy-4-hydroxy-phenylglycol piperazine salt,4-hydroxy-3-methoxyphenylglycol-4-sulfate potassiumsalt,3-methoxy-4-hydroxyphenylglycol-4-sulfate potassium salt,normetanephrine HCl, pindobind,(+)-, prazobind,threo-dihydroxyphenylserine(+)-, and xylamine HCl.

Cholinergics are compounds that are agonists or antagonists ofsubstances capable of stimulating or activating nerve systems that areactivated by acetyl choline. Cholinergics include both cholinergicagonists and cholinergic antagonists. Examples of cholinergic agonistsinclude acetylcholine chloride, arecoline HBr, bethanechol chloride,carbachol, cis-dioxolane,(+)-, (4-hydroxy-2-butynyl)-1-trimethylammoniumm-chlorocarbonilate chloride, methacholine chloride, metoclopramide HCl,muscarine chloride,(±)-, muscarine chloride(+)-, nicotinetartrate,S(−)-, cis-2-methyl-5-trimethylammoniummethyl-1,3-oxathiolaneiodide (OXA-22), oxotremorine, oxotremorine sesquifumarate, andpilocarpine HCl, (+)-.

Examples of cholinergic antagonists include atropine sulfate,benztropine mesylate, 4-diphenylacetoxy-N-methylpiperidine methiodide,dexetimide HCl, S(+)-, levetimide HCl, R(−)-, ipratropium bromide,mecamylamine HCl, methoctramine HCl, pirenzepine HCl,RS(±)-quinuclidinyl benzilate, R(-)-quinuclidinyl benzilate,S(+)-quinuclidinyl benzilate, RS(+)-3-quinuclidinylxanthene-9-carboxylate hemioxalate, scopolamine HBr,(−)-, scopolamineHBr,(+)-, scopolamine n-butyl bromide,(−)-, scopolamine methylbromide,(−)-, scopolamine methyl bromide,(+)-, succinylcholine chloride,d-tubocurarine chloride, tetraethylammonium chloride. Other cholinergicdrugs include acetylethylcholine mustard hydrochloride, N-aminodeanolHCl, eseroline fumarate, hemicholinium-3, vesamicol HCl, (±)-, vesamicolHCl, (−)-, and vesamicol HCl, (+)-.

Benzodiazepines are a type of tranquilizer having a common molecularstructure of phenylthiazines and similar pharmacological activities suchas anti-anxiety, muscle relaxing, sedative, and hypnotic effects.Benxodiazepines include benzodiazepine agonists, benzodiazepineantagonists and benzodiazepine inverse agonists. Examples ofbenzodiazepine agonists include chlordiazepoxide HCl, diazepam,flurazepam HCl, and flunitrazepam.

An example of a benzodiazepine antagonist is peripheral benzodiazepineantagonist and examples of benzodiazepine inverse agonists include ethylβ-carboline-3-carboxylate (β-CCE), methyl β-carboline-3-carboxylate(β-CCM), propyl β-carboline-3-carboxylate (β-CCP),3-hydroxymethyl-β-carboline 3-HMC,methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM),N-methyl-β-carboline-3-carboxamide (FG-7142). Other benzodiazepinesinclude BZ receptor preparation, diazepam,desmethyl-, chlorazepate,diazepam, and oxazepam.

Drugs effecting cocaine receptors are substances which interact orinterfere in some manner with a cocaine receptor. Examples of such drugsinclude buprenorphine, cocaine HCl, ecgonidine methyl ester, ecgonineHCl, CFT naphthalene disulfonate (WIN 35,428).

Drugs effecting cyclic nucleotide pathways are substances which interactor interfere in some manner with the cyclic nucleotide pathways.Examples of such drugs include forskolin,forskolin,7β-[γ-(morpholino)-butyryl]-,forskolin,6β-[piperidino-propionyl]-, and forskolin,1,9-dideoxy-.

Dopaminergics are drugs which in some manner effect, interact, orinterfere with the dopaminergic pathways. The term is intended toinclude both dopamine agonists and dopamine antagonists. Dopamineagonists include N-allylnorapomorphine HBr,R(−)-,(±)-2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide(5,6-ADTN HBr), (±)-2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide (6,7-ADTN HBr), apocodeine HCl, R(−)-, apomorphine HCl,R(−)-, bromocriptine mesylate,(±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrobromide;6-chloro-N-allyl-SDK-38393 hydrobromide,(±)-2-dimethylamino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide (M-7),(±)-2-dimethylamino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide (TL-99),(±)-2-dipropylamino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide, dipropyldopamine HBr, dopamine HCl, 2-hydroxyapomorphineHBr,R(−)-, R(−)-10,11-methylenedioxy-N-n-propylnoraporphinehydrochloride, N-methyldopamine HCl,(epinine), morphothebaine HCl,(±)-2-(N-phenylethyl-N-propyl)amino-5-hydroxytetralin hydrochloride,R(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride,S(−)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride,propylnorapomorphine HCl, R(−)- (NPA), quinpirole HCl,1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride,R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diolhydrochloride,S(−)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diolhyrdrochloride,(±)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benz azepinehydrochloride, tyramine HCl, and m-tyramine HCl.

Dopamine antagonists include amoxapine, apomorphine HCl, S(+)-,azidoclebopride, bulbocapnine,(+)-, butaclamol HCl, (+)-, butaclamolHCl, (−)-, domperidone, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline,eticlopride HCl, S(−)-, eticlopride HCl, R(+)-, fluphenazine HCl,flupentixol,cis(Z)-, fluspirilene, haloperidol, haloperidol, chlorinatedanalog, metoclopramide HCl, pimozide, prochlorperazine dimaleate,propylnorapomorphine HCl, S(+)- (NPA),R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetra-hydro-1H-3-benzazepinehydrochloride,S(−)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride,(±)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, spiperone HCl, sulpiride,(±)-, sulpiride,S(−)-,sulpiride,R(+)-, thiothixine HCl, trifluoperazine HCl, trifluoperidolHCl, thioridazine. Other dopaminergics include amantadine HCl, amfonelicacid, bupropion HCl, γ-butyrolactone, chloroethylnorapomorphine HCl,L-3,4-dihydroxyphenylalanine (L-DOPA), D-3,4-dihydroxyphenylalanine(DOPA,D-), L-3,4-dihydroxyphenylalanine methyl ester hydrochloride,3,4-dihydroxyphenylacetic acid (DOPAC),1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazinedihydrochloride, haloperidol metabolite I, haloperidol metabolite II,haloperidol metabolite III, homovanillic acid, 3-O-methyldopamine HCl,4-O-methyldopamine HCl, nomifensine, reserpine, andtetrahydro-L-biopterin HCl.

Enzyme inhibitors are substances which inhibit an enzymatic reaction.Examples of enzyme inhibitors include edrophonium chloride,N-methylphysostigmine,(−)-, neostigmine bromide, physostigmine sulfate,tacrine HCL (THA), tacrine,1-hydroxy maleate, iodotubercidin,p-bromotetramisole,(−)-, 10-(α-diethylaminopropionyl)-phenothiazinehydrochloride (As-1397), calmidazolium chloride, hemicholinium-3,3,5-dinitrocatechol (OR-486), diacylglycerol kinase inhibitor I(R59022), diacylglycerol kinase inhibitor II (R59949),3-phenylpropargylamine, N⁶-monomethyl-L-arginine acetate, carbidopa,3-hydroxybenzylhydrazine HCl (NSD-1015), hydralazine HCl (apresoline),clorgyline HCl, deprenyl HCl, L(−)-, deprenyl HCl, D(+)-, hydroxylamineHCl, iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-indole, nialamide,pargyline HCl, quinacrine HCl, semicarbazide HCl, tranylcypromine HCl,N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride,3-isobutyl-1-methylxanthne, papaverine HCl, indomethacind,2-cyclooctyl-2-hydroxyethylamine hydrochloride (CONH),(±)-2,3-dichloro-α-methylbenzylamine (DCMB),(LY-78335),8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride,p-aminoglutethimide,(±)-, p-aminoglutethimide tartrate,R(+)-,p-aminoglutethimide tartrate,S(−)-, 3-iodotyrosine,L-,α-methyltyrosine,L-, α-methyltyrosine,D L-, and allopurinol.

Excitatory amino acids are amino acids used to activate or exciteneurons involved in the glutaminergic or aspartic acid stimulatedpathways. Excitatory amino acids include both agonists and antagonists.Exictatory amino acid agonists include(R,S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrobromide,(R,S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, asparticacid,L-, glutamic acid HCl, L-, glutamic acid diethyl ester HCl, L-,ibotenic acid, kainic acid, N-methyl-D-aspartic acid (NMDA),cis-piperidine-2,3-dicarboxylic acid, and quisqualic acid,(+)-.

Excitatory amino acid antagonists include3-amino-1-hydroxy-2-pyrrolidone (HA-966), 7-chlorokynurenic acid,6-cyano-7-nitroquinoxaline-2,3-dione, dextromethorphan HBr, dextrorphan,6,7-dinitroquinoxaline-2,3-dione, 5-fluoroindole-2-carboxylic acid,kynurenic acid, 2-amino-3-phosphonopropionic acid (AP-3),(±)-2-amino-4-phosphonobutyric acid (AP-4), 2-amino-5-phosphonopentanoicacid (AP-5), (±)-2-amino-7-phosphonoheptanoic acid (AP-7),(±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, ketamine HCl,(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohep-ten-5,10-iminehydrogen maleate,(−)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohep-ten-5,10-iminehydrogen maleate.

GABA-ergics are substances capable of interacting in some manner withneurons that have gamma-aminobutyric acid receptors. GABA-ergics includeboth GABA agonists and GABA antagonists. Examples of GABA agonistsinclude baclofen,(±)-, γ-aminobutyric acid (GABA), isoguvacine HCl,isonipecotic acid, kojic amine, muscimol HBr, piperidine-4-sulfonicacid, thiomuscimol HBr, and4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol HCl.

Examples of GABA antagonists include 5-aminovaleric acid HCI,bicuculline, bicuculline methchloride, bicuculline methbromide,bicuculline methiodide, 2-hydroxysaclofen, phaclofen,2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide.Other GABA-ergics include 4-aminopyridine, butylbicyclophosphorothionate(TBPS), GABA receptor preparation, guvacine HCl, cis-4-hydroxynipecoticacid, γ-hydroxybutyric acid, nipecotic acid,(+)-, pentylenetetrazole,picrotoxin, and 4,5,6,7-tetrahydroisoxazolo[4,5-clpyridin-3-ol (THPOHBr).

Histaminergics are substances which interact or interfere in some mannerwith histamine and/or histamine receptors. Histaminergics include bothhistamine agonists and histamine antagonists. Histamine agonists includedimaprit, histamine HCl, histamine, α-methyl oxalate,R(−)-. Histamineantagonists include cimetidine, chlorpheniramine maleate,(±)-,chlorpheniramine maleate,(+)-, cyproheptadine HCl, ranitidine HCl,pyrilamine maleate. Other histaminergics include histidine HCl, L-, andhistidine HCl, D-.

Ion channel modulators are compounds that modify the activity ofreceptors controlling the flow of ions into cells. Ion channelmodulators include both ion channel activators and ion channelantagonists. An example of an ion channel activator includes1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)-phenyl]-3-pyridinecarboxylicacidmethyl ester. Examples of ion channel antagonists include amilorideHCl, amiloride,5-(N,N-dimethyl)HCl, amiloride,5-(N,N-hexamethylene)-,amiodarone HCl, benzamil HCl, bepridil HCl, clofilium tosylate,ω-conotoxin GVIA, cyproheptadine HCl, diltiazem HCl,R(+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-7-yl),oxy]aceticacid, flunarizine HCl, fluspirilene,R(+)-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-oxy]aceticacid, lidocaine N-ethyl iodide, methoxyverapamil HCl, (±)-,methoxyverapamil HCl, S(−)-, methoxyverapamil HCl, R(+)-, nifedipine,pimozide, ryanodine, 8-(diethylamino)octyl-3,4,5-trimethoxybenzoatehydrochloride, verapamil HCl, (±)-, verapamil HCl, S(−)-, verapamil HCl,R(+)-. Other ion channel modulators include calmidazolium chloride,fluphenazine N-mustard, phenoxybenzamine HCl, trif luoperazine HCl,N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride,N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide hydrochloride,D(+)-myo-inositor-1,4,5-triphosphate (synthetic),N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride,1-(5-isoquinolinesulfonyl)-2-methylpiperazine kihydrochloride,N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride,N-(2-aminoethyl)-5-isoquinolinesulfonamide dihydrochloride,diacylglycerol kinase inhibitor I (R59022), diacylglycerol kinaseinhibitor II (R59949), andN-(n-heptyl)-5-chloro-1-naphthalenesulfonamide.

Neurotoxins are substances which have a toxic effect on the nervoussystem, e.g. nerve cells. Neurotoxins include adrenergic neurotoxins,cholinergic neurotoxins, dopaminergic neurotoxins, and otherneurotoxins. Examples of adrenergic neurotoxins includeN-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride. Examples ofcholinergic neurotoxins include acetylethylcholine mustard hydrochlorideacetyl AF-64. Examples of dopaminergic neurotoxins include6-hydroxydopamine HBr,1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydro-pyridine hydrochloride,1-methyl-4-phenyl-2,3-dihydropyridinium perchlorate,N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine HCl,1-methyl-4-phenylpyridinium iodide. Other neurotoxins includeL-β-methyl-α,β-diaminopropionic acid hydrochloride,(±)-β-methyl-α,β-diaminopropionic acid hydrochloride,L-β-oxalyl-α,β-diaminopropionic acid, and quinolinic acid.

Opioids are substances having opiate like effects that are not derivedfrom opium. Opioids include opioid agonists and opioid antagonists.Opioid agonists include codeine sulfate, fentanyl citrate, hydrocodonebitartrate, loperamide HCl, morphine sulfate, noscapine, norcodeine,normorphine, thebaine. Opioid antagonists include nor-binaltorphimineHCl, buprenorphine, β-chlornaltrexamine 2HCl, β-funaltrexamione HCl,nalbuphine HCl, nalorphine HCl, naloxone HCl, naloxonazine, naltrexoneHCl, and naltrindole HCl (NTI).

Drugs effecting PCP/Sigma receptors include both receptor agonists andreceptor antagonists. Receptor agonists include N-allylnormetazocineHCl, (+)-(SKF-10047), N-allylnormetazocine HCl, (−)-,1,3-Di(2-tolyl)guanidine(DTG), phencyclidine HCl,1-[1-(2-thienyl)cyclohexyl]piperidine hydrochloride (TCP). Receptorantagonists include metaphit methanesulfonate, andR(+)-3-(3-hydroxyphenyl)-N-propylpiperidine hydrochloride.

Serotonergics are substances that interact or interfere in some mannerwith nerve cells having serotonin receptors. serotonergics includeserotonin agonists and other serotonergics. Serotonin agonists includecarboxamidotryptamine maleate (5-CT), 1-(3-chlorophenyl)piperazine HCl,7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinosaline,1:2maleate salt, dipropyl-5-carboxamidotryptamine (DP-5-CT),(±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl,(±)-1-(4-bromophenyl-2,5-dimethoxy)-2-aminopropane hydrobromide,1-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride (DMA),(+-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaleneHBr,(±)-8-hydroxydipropylaminotetralin HBr,5-methoxy-N,N-dimethyltryptamine hydrogen oxalate,1-(2-methoxyphenyl)piperazine HCl, 5-methoxytryptamine HCl,2-methylserotonin maleate, α-methylserotonin maleate,p-aminophenylethyl-m-trifluoromethylphenylpiperazine;4[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]benzeneamine,1-phenylbiguanide, quipazine maleate serotonin creatinine sulfate,serotonin HCl, serotonin oxalate, spiroxatrine,m-trifluoromethylphenylpiperazine hydrochloride, cyproheptadine HCl,3-tropanyl-indole-3-carboxylate (ICS 205,930),3-tropanyl-indole-3-carboxylate methiodide, ketanserin tartrate,3-tropanyl-3,5-dichlorobenzoate (MDL-72222), metoclopramide HCl,mianserin HCl, 1-(l-naphthyl)piperazine HCl, pirenperone, propranololHCl, S(−)-, propranolol HCl, R(+)-, propranolol HCl, (±)-, ritanserin,spiperone HCl, zacopride maleate. Other serotonergics includep-chlorophenylalanine, clomipramine HCl, fenfluramine,S(+)-,fenfluramine,R(−)-, 5-hydroxy-L-tryptophan, imipramine HCl,L-tryptophan, zacopride maleate,(±)-, and zimelidine HCl.

Hypnotics are substances which produce a hypnotic effect. Hypnoticsinclude pentobarbital sodium, phenobarbital, secobarbital, thiopentaland mixtures, thereof, heterocyclic hypnotics, dioxopiperidines,glutarimides, diethyl isovaleramide, α-bromoisovaleryl urea, urethanesand disulfanes.

Psychic energizers are substances that raise the energy level of thebrain, such as compounds that raise the level of ATP or inhibit itsbreakdown in nerve cells. Examples of psychic energizers includeisocarboxazid, nialamide, phenelzine, imipramine, amitryptylinehydrochloride, tranylcypromine, pargylene, and protryptylinehydrochloride.

Tranquilizers are substances which provide a tranquilizing effect.Examples of tranquilizers include chloropromazine, promazine,fluphenzaine, reserpine, deserpidine, and meprobamate.

Anticonvulsants are substances which have an effect of preventing,reducing, or eliminating convulsions. Examples of such agents includeprimidone, phenytoin, valproate, Chk and ethosuximide.

Muscle relaxants and anti-parkinson agents are agents which relaxmuscles or reduce or eliminate symptoms associated with Parkinson'sdisease. Examples of such agents include mephenesin, methocarbomal,cyclobenzaprine hydrochloride, trihexylphenidyl hydrochloride,levodopa/carbidopa, and biperiden.

Antihypertensives are substances capable of counteracting high bloodpressure. Examples of such substances include α-methyldapa and thepivaloyloxyethyl ester of α-methyldapa.

Analgesics are substances capable of preventing, reducing, or relievingpain. Examples of analgesics include morphine sulfate, codeine sulfate,meperidine, and nalorphine.

Antipyretics are substances capable of relieving or reducing fever andanti-inflammatory agents are substances capable of counteracting orsuppressing inflammation. Examples of such agents include aspirin(salicylic acid), indomethacin, sodium indomethacin trihydrate,salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal,diclofenac, indoprofen and sodium salicylamide.

Local anesthetics are substances which have an anesthetic effect in alocalized region. Examples of such anesthetics include procaine,lidocain, tetracaine and dibucaine.

Antispasmodics and muscle contractants are substances capable ofpreventing or relieving muscle spasms or contractions. Examples of suchagents include atropine, scopolamine, oxyphenonium, and papaverine.

Prostaglandins are art recognized and are a class of naturally occurringchemically related, long-chain hydroxy fatty acids that have a varietyof biological effects. Examples of such agents include E2, and E1.

Anti-bacterials are substances which destroy or suppress the growth orreproduction of bacteria. Examples of anti-bacterials includetrimethoprin, sulfamethoxazole, cefoperazone, chloroamphenicol,polymycin, and metronidazole.

Antiseptics are substances capable of inhibiting the growth anddevelopment of microorganisms without necessarily destroying them.Examples of antiseptics include those discussed above as anti-bacterialsand other sulfonamide substances.

Anti-depressants are substances capable of preventing or relievingdepressant. Examples of anti-depressants include imipramine,amitriptyline, nortriptyline, protriptyline, desipramine, amoxapine,doxepin, maprotiline, tranylcypromine, phenelzine, and isocarboxazide.

Anti-migraine preparations are substances capable of preventing orrelieving migraine headaches. Examples of such substances include.ergotamine tartrate, caffeine, dihydroengotamine mesylate propanololHCl, acetominophin, and salicylic acid.

Central nervous system stimulants are substances capable of stimulatingthe central nervous system. Examples of such substances includeamphetamine, phenylalanine, picrotoxinin, and methylphenidate.

Imaging agents are agents capable of imaging a desired site, e.g. tumor,in vivo. Examples of imaging agents include substances having a labelwhich is detectable in vivo, e.g. antibodies attached to fluorescentlabels. The term antibody includes whole antibodies or fragmentsthereof.

Specific targeting agents include agents capable of delivering atherapeutic agent to a desired site, e.g. tumor, and providing atherapeutic effect. Examples of targeting agents include agents whichcan carry toxins or other agents which provide beneficial effects. Thetargeting agent can be an antibody linked to a toxin, e.g. ricin A or anantibody linked to a drug.

The term protein is art-recognized and for purposes of this inventionalso encompasses peptides. Examples of proteins include antibodies,hormones, and growth factors, e.g. nerve growth factors and an exampleof a peptide includes nerve growth factor peptide.

The proteins or peptides may be any bioactive protein or peptide,naturally occurring or synthetic. The term peptide is intended toinclude the classes of peptides known as neuropeptides and regulatorypeptides. Specific examples of such factors include growth hormone andgrowth hormone-releasing hormone, gonadotorpin-releasing hormone, andits agonist and antagonist analogues, somatostatin and its analogues,gonadotropins such as luteinizing hormone and follicle-stimulatinghormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon,vasopressin, oxytocin, alpha and beta melanocyte-stimulating hormones,peptide molecules which stimulate erythrocytes, leucotyte and immunocytegrowth and function such as colony stimulating factors (CFS 1 and 2),erythropoitin and lymphokines (including interleukin I and II),angiotensin I and II, bradykinin, kallidin, adrenocorticotropic hormone,thyroid stimulating hormone, insulin, glucagon and the numerousanalogues and congeners of the foregoing peptides. It should beunderstood that the term peptide is intended to include small proteinsand particularly those molecules having on the order of about 100 aminoacids or less. Other larger proteins are intended to be encompassed bythe term protein.

The protein or peptide preferably has a molecular weight of less thanabout 5,000 and more preferably less than about 1,500.

Anti-viral agents are substances capable of destroying or suppressingthe replication of viruses. Examples of anti-viral agents includeα-methyl-1-adamantane methylamine (ri mantadine),1-3-D-ribofuranosyl-1,2,4-triazole-3 carboxamide (ribavirin),9-[2-hydroxy-ethoxy]methylguanine (Acyclovir), adamantanamine, and5-iodo-2′-deoxyuridine (Idoxuridine), adenine arabinoside (Vidarabine)and interferon, synthetic or naturally occurring.

Anti-psychotic agents are substances which modify psychotic behavior.Examples of such agents include phenothiazines, butyrophenones andthioxanthenes.

Anti-emetics are substances which prevent or alleviate nausea orvomiting. An example of such a substance includes dramamine.

The examples discussed above may be listed in the salt or non-salt formbut for purposes of this invention both forms are intended to beencompassed. Further, if a particular salt-form of a drug, e.g. naloxoneHCl, is listed, other art recognized biologically accepted salts can beused in place of the listed salt-form. Examples of acceptable saltsinclude hydrochlorides, hydrobromine, sulfate, laurelate, palmatate,phosphate, nitrate, borate, acetate, maleate, tartrate, oleate,salisilate, salts of metals, means or organic cations, e.g. quarternaryammonium.

This invention is also intended to encompass derivatives or equivalentsof the above discussed drugs. A derivative is a drug which isstructurally similar to the foregoing list of drugs and is capable ofachieving the same or substantially the same function or activity. Anequivalent is an agent capable of achieving the same or substantiallythe same intended function or activity.

The drug compound and carrier may be coupled using a variety ofreactions involving treating the neuroactive compound (or a protectedderivative thereof) having one, free hydroxyl or amino group with thecorresponding fatty acid carrier or an activated derivative thereof. Forexample, a dopamine derivative having its two hydroxyl groups protectedwith acetonide may be reacted with the carrier in the presence of awater-removing compound such as dicyclohexyl carbodiimide in a solventsuch as dioxane, tetrahydrofurane and methylpyrrolidone or N,Ndimethylformamide at ambient temperature. The solvent then may beremoved and the desired product may be extracted from the formeddicyclohexylurea using a suitable solvent such as methylene chloride.The protecting group then may be removed by treatment with a suitableacid such as 4N HCl in dioxane. The amine group of a neuroactivecompound may be coupled to the carboxyl group of the carrier also byusing the acid chloride or a low carbon ester derivative of the carrierand forming amide bonds by liberating HCl or an alcohol respectively.Drugs containing alcohol groups (OH) may be coupled via ester bonds tothe fatty acid carrier by similar procedures as described above (e.g.using the anhydride derivative, the acid chloride derivative for thefree acid of the carrier). Alternate couplings such as phosphoramide,sulfate, sulfonate, phosphate or urethane also may be used as will berecognized by one of ordinary skill in the art to coupled carriermolecules to drugs.

Amide bonds are preferred because they may survive the environment ofthe stomach and the prodrug may be administered orally. However, itshould be recognized that bonds incapable of surviving the environmentof the stomach such as an ester bond still may be used to link thecarrier of the invention and a drug, with the resulting conjugatecapable of crossing the blood brain barrier. Such a prodrug may beinjected or protected from the environment of the stomach by, forexample, coatings, well-known to those skilled in the art. Such acoating may be called for even in the presence of an amide bond betweenthe carrier and the drug.

The compounds of the invention can be prepared in pharmaceuticalpreparations containing the compounds themselves and a pharmaceuticallyacceptable carrier. Such carriers include those that facilitateadministration of the prodrug, prolong shelf life of the prodrug, allowa particular mode of administration of the prodrug, or provide orfacilitate formulation of a particular dose of the prodrug. Thepharmaceutically acceptable carrier may be solid or liquid. Examples ofliquid carriers include water, an aqueous solution of non-toxic salts,such as sterile physiological solutions of saline, or aqueous solutionscontaining organic solevents, such as ethanol. Also suitable areemulsions, such as oil-in-water emulsions. Solid carriers include bothnutritative carriers, such as sucrose or gelatin, and non-nutritativecarriers, such as cellulose or talc. Such carriers, for example, permitformation of tablets containing a particular dose of the prodrug. Alsoincluded are carriers of the implantable-type which permitsustained-release of the prodrug.

Slow-release capsules and other protective mediums are suitable for theoral administration of the compounds of the invention due to theprotection afforded against hydrolysis in the gastrointestinal tract.Preferred are those capsules which permit the compounds to bypass thestomach. When the present compounds are to be administered peritoneally,they can be administered by subcutaneous, intramuscular or intravenousinjections.

Amounts of the compounds of the invention useful for promoting theuptake of the drug by the brain may vary from individual to individual,as well as varying from the particular disorder being treated and theparticular effect desired. Such amounts can be determined byexperimentation as is well understood by those skilled in thepharmaceutical arts. For suppressing appetite with Dopamine conjugates,amounts in the range of about 100-20000 micro grams per kilogram bodyweight are preferred.

Generally, compounds are most active when administered intravenouslythan by the other preferred routes. However, when an amide bond is usedto conjugate the drug and carrier, oral administration of the drugappears to work quite well. In any event, when the conjugates of theinvention are used to promote the uptake of a drug into the centralnervous system, they are administered to humans in amounts sufficient topromote the crossing of the blood brain barrier. When the therapyinvolves restoring a deficiency of a neuro-transmitter in a human, theconjugate is administered in an amount sufficient to cause thenormalization of the deficiency. When the compounds of the presentinvention are used for treating Parkinsonism or hyperprolactinemia orfor suppressing appetite, then they are administered to a human in needof such treatment in an amount sufficient to affect the desired result.

Administration, of course, may be made by any method which allows theactive compound to reach the bloodstream and penetrate through the bloodbrain barrier. Typical methods include oral, rectal, peritoneal andtopical administration of the compounds. When the compounds areadministered orally, the composition can be in the form of dragees,tablets, syrups or ampules. When the compounds are administeredrectally, the composition can be in the form of a suppository. Inaddition, when the compounds of the invention are to be administered bytopical application, they can be in the form of pomade or a gel.

The ability of the bond between the drug and the carrier to be brokenonce the prodrug is in the CNS will influence the choice of bonds.Likewise, the desired delivery site in the CNS may affect the choice ofbonds as the enzymes responsible for breaking various bonds areconcentrated in particular locations.

Variations of the particular carrier described in the preferredembodiment also are contemplated. For example, it has been found that astraight chain fatty acid that does not occur naturally in the brain andhaving 12 carbon atoms and no double bonds coupled to dopamine does noteffectively cross the blood brain barrier and is completely inactive asan appetite-suppressant. Likewise, another straight chain fatty acidthat does not occur naturally in the brain and having 22 carbon atomsand no double bonds coupled to dopamine does not effectively cross theblood brain barrier and is essentially inactive as anappetite-suppressant. However, a straight chain fatty acid occurringnaturally in the brain and having 18 carbon atoms and 3 double bondscoupled to dopamine is partially active. This molecule crosses the bloodbrain barrier, and it has some effect on locomotor activity although nosubstantial effect on appetite. Thus, it appears that the length of thefatty acid, the degree of saturation and whether the fatty acid isnaturally occurring in the brain affects the ability of the carrier tobe combined with a drug to form a prodrug that will cross the bloodbrain barrier and effectively deliver and liberate the drug at an activesite. The carrier molecule preferably is a straight-chained fatty acidof between 16 and 26 carbon atoms in length. More preferably the carriermolecule is between 16 and 22 carbon atoms in length and occursnaturally in the brain. Among the fatty acids occurring naturally in thebrain are those with 16 carbon atoms and 0, 1 or 2 double bonds (C16:0;C16:1 and C16:2), those with 18 carbon atoms and 1, 2 or 3 double bonds(C18:1; C18:2; and C18:3), those with 20 carbon atoms and 1, 2 or 4double bonds (C20:1; C20:2; and C20:4) and those with 22 carbon atomsand 4, 5 or 6 double bonds (C22:4; C22:5 and C22:6). While the positionof the double bonds may be between any of the carbon atoms in the fattyacids, the preferred loci are those which occur naturally in the fattyacids of the CNS. Among the naturally-occurring fatty acids, C16:0 andC22:6 are preferred due to their preference for concentrating in thesynaptosomal membranes, with C22:6 most preferred. It also has beenfound that C18:3 acts above average in its ability to deliver a compoundacross the blood brain barrier.

The fatty acids of this invention include both substituted andunsubstituted fatty acids. In the substituted fatty acid, at least onehydrogen along the fatty acid chain is replaced with a substituent.Examples of such substituents include alkyl groups, e.g. methyl, ethyl,propyl, isopropyl, butyl, and pentyl. Only those substituents that donot greatly adversely effect the ability of the carrier to perform itsintended functions, including crossing the blood brain barrier and/ortargeting the drug to a particular area of the brain, e.g. D₂ receptors,can be used. In addition to the foregoing fatty acids, branched chainfatty acids having between 16 and 26 carbon atoms may be used.Particular examples include analogues of the naturally-occurringpolyisoprenoids (dolicols) such as

This invention further pertains to methods for introducing a drug intothe central nervous system. The method comprises introducing apharmaceutically effective amount of the prodrugs described above intothe bloodstream of a patient. A pharmaceutically effective amount isthat amount necessary to prevent, treat, or reduce the symptomsassociated with a particular condition or disease being treated.

This invention also pertains to methods for manufacturing pharmaceuticalpreparations, including coupling a fatty acid to a drug to form aprodrug, and then forming a pharmaceutical dose containing the prodrugand a pharmaceutically acceptable carrier.

Having now fully described this invention, it will be appreciated bythose of ordinary skill in the art that the same can be practiced with awide and equivalent range of compositions, modes of administration,therapeutic treatments and the like, without affecting the spirit orscope of the invention or any embodiment thereof.

What is claimed is:
 1. A compound comprising: a fatty acid coupled to ananti-aids substance, antibiotic, cholinergic agonist benzodiazepine,drug effecting cocaine receptors, enzyme inhibitor, excitatory aminoacid antagonist, GABA-ergic antagonist, histaminergic antagonist, ionchannel modulator, neurotoxin, opioid, drug affecting PCP/Sigmareceptors, hypnotic agent, phsychic energizer, tranquilizer,anti-convulsant, muscle relaxant, anti-hypertensive agent, anti-pyreticagent, anti-inflammatory agent, local anesthetic, muscle contractant,prostaglandin, anti-bacterial agent, anti-septic agent, anti-depressant,anti-migraine agent, imaging agent, specific targeting agent, protein,anti-viral agent, anti-addition agent, or anti-emetic agent, wherein thecompound is capable of passing across the blood brain barrier.
 2. Thecompound of claim 1, wherein said fatty acid is selected from the groupconsisting of C16:0; C 16:1; C16:2; C18:1; C18:2; C18:3; C20:1; C20:2;C20:3; C20:4; C22:4; C22:5; C22:6, and C24:4.
 3. A prodrug compound asclaimed in claim 1 or 2 wherein the fatty acid carrier occurs naturallyin the brain.
 4. A pharmaceutical preparation containing the compound ofclaim 1 or 2 and a pharmaceutically acceptable carrier.
 5. A method forintroducing a drug into the central nervous system comprising,introducing the compound of claim 1 or 2 into the blood stream of apatient.
 6. The compound of claim 1, wherein the drug is an anti-AIDSsubstance.
 7. The compound of claim 1, wherein the drug is anantibiotic.
 8. The compound of claim 1, wherein the drug is acholinergic agonist.
 9. The compound of claim 1, wherein the drug is abenzodiazepine.
 10. The compound of claim 1, wherein the drug is a drugeffecting cocaine receptor.
 11. The compound of claim 1, wherein thedrug is an enzyme inhibitor.
 12. The compound of claim 1, wherein thedrug is an excitatory amino acid antagonist.
 13. The compound of claim1, wherein the drug is a GABA-ergic antagonist.
 14. The compound ofclaim 1, wherein the drug is a histaminergic antagonist.
 15. Thecompound of claim 1, wherein the drug is an ion channel modulator. 16.The compound of claim 1, wherein the drug is a neurotoxin.
 17. Thecompound of claim 1, wherein the drug is an opioid.
 18. The compound ofclaim 1, wherein the drug is a drug affecting PCP/Sigma receptor. 19.The compound of claim 1, wherein the drug is an hypnotic agent.
 20. Thecompound of claim 1, wherein the drug is a phsychic energizer.
 21. Thecompound of claim 1, wherein the drug is a tranquilizer.
 22. Thecompound of claim 1, wherein the drug is an anti-convulsant.
 23. Thecompound of claim 1, wherein the drug is a muscle relaxant.
 24. Thecompound of claim 1, wherein the drug is an anti-hypertensive agent. 25.The compound of claim 1, wherein the drug is a anti-pyretic agent. 26.The compound of claim 1, wherein the drug is an anti-inflammatory agent.27. The compound of claim 1, wherein the drug is a local anesthetic. 28.The compound of claim 1, wherein the drug is a muscle contractant. 29.The compound of claim 1, wherein the drug is a prostaglandin.
 30. Thecompound of claim 1, wherein the drug is an anti-bacterial agent. 31.The compound of claim 1, wherein the drug is an anti-septic agent. 32.The compound of claim I, wherein the drug is an anti-depressant.
 33. Thecompound of claim 1, wherein the drug is an anti-migraine agent.
 34. Thecompound of claim 1, wherein the drug is an imaging agent.
 35. Thecompound of claim 1, wherein the drug is a specific targeting agent. 36.The compound of claim 1, wherein the drug is a protein.
 37. The compoundof claim 1, wherein the drug is an anti-viral agent.
 38. The compound ofclaim 1, wherein the drug is an anti-addiction agent.
 39. The compoundof claim 1, wherein the drug is an anti-emetic agent.
 40. The compoundof claim 1, wherein the fatty acid is C16:0.
 41. The compound of claim1, wherein the fatty acid is C16:1.
 42. The compound of claim 1, whereinthe fatty acid is C16:2.
 43. The compound of claim 1, wherein the fattyacid is C18:1.
 44. The compound of claim 1, wherein the fatty acid isC18:2.
 45. The compound of claim 1, wherein the fatty acid is C18:3. 46.The compound of claim 1, wherein the fatty acid is C20:1.
 47. Thecompound of claim 1, wherein the fatty acid is C20:2.
 48. The compoundof claim 1, wherein the fatty acid is C20:3.
 49. The compound of claim1, wherein the fatty acid is C20:4.
 50. The compound of claim 1, whereinthe fatty acid is C22:4.
 51. The compound of claim 1, wherein the fattyacid is C22:5.
 52. The compound of claim 1, wherein the fatty acid isC22:6.
 53. The compound of claim 1, wherein the fatty acid is C24:4.